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For the layout of the new theme there are two things we should consider.

What type of layout mechanics should we use?

Traditional floats layout - using the standard grid we see everyday

Table Layout - using display: table based grid compatible with (IE9^)

Flex Layout - using display: flex based grids compatible with (IE10^)

How to implement it?

Class based - this relies on classes applied to markup to set layout

Mixin based - This uses the grid system as mixins that are applied to the components

Best of both - Uses classes to set major barebones of the layout and mixins for layout of components.

My Thoughts
Personally I am leaning to options 3 for both questions but I want to hear everyones thoughts on the matter.

My reasonings for choosing flex is that its far more versatile and once you get used to it easier to use.

My reasonings for using both classes and mixins is that there are things with the layout that should be more stringent and require more knowledge when messing with and classes provide more control. This would be for the skeleton of the theme. The sections of the page. However the components are meant to be self containing and should opt to use as few objects as possible which is what the grid classes would be objects. They would not be singletons like that of the buttons class which are essentially tiny components themselves, but rather pattern based objects as that is what a grid is.

I tend to agree with your thoughts. Flex layout is definitely the way to go for a future front-end style and (judging my having worked with bootstrap for a bit now) I also think that having both classes and mixins gives you better control over specific parts of the front-end.